Hypoxia promotes production of neural crest cells in the embryonic head

Abstract

Hypoxia is encountered in either pathological or physiological conditions, the latter of which is seen in amniote embryos prior to the commencement of a functional blood circulation. During the hypoxic stage, a large number of neural crest cells arise from the head neural tube by epithelial-to-mesenchymal transition (EMT). As EMTlike cancer dissemination can be promoted by hypoxia, we investigated whether hypoxia contributes to embryonic EMT. Using chick embryos, we show that the hypoxic cellular response, mediated by hypoxia-inducible factor (HIF)-1α, is required to produce a sufficient number of neural crest cells. Among the genes that are involved in neural crest cell development, some genes are more sensitive to hypoxia than others, demonstrating that the effect of hypoxia is gene specific. Once blood circulation becomes fully functional, the embryonic head no longer produces neural crest cells in vivo, despite the capability to do so in a hypoxia-mimicking condition in vitro, suggesting that the oxygen supply helps to stop emigration of neural crest cells in the head. These results highlight the importance of hypoxia in normal embryonic development.

Hypoxia and hyperoxia differentially control proliferation of rat neural crest stem cells via distinct regulatory pathways of the HIF1α–CXCR4 and TP53–TPM1 proteins

“…Previous studies have shown that HIF1α and its downstream effector CXCR4 both up‐regulate proliferation of various tumor and progenitor cells (Carmeliet et al, ; Goda et al, ; Kahn et al, ; Nombela‐Arrieta et al, ; Park et al, ; Xia et al, ; Guimaraes‐Camboa et al, ), and also up‐regulate chemotaxis, migration, and EMT of neural crest stem/progenitor cells in zebrafish, Xenopus and chick embryos as well as mouse hair follicles (Belmadani et al, ; Rezzoug et al, ; Barriga et al, ; Singleton Escofet, ; Scully et al, ). Hence, we were interested in analyzing HIF1α and CXCR4 expression in rNCSCs under various oxygen tensions.…”

“…Previous studies have demonstrated that S100A2 may compete with F‐actin for binding to tropomyosins in microvilli in the cytoplasm of LLC PK1 cells (Gimona et al, ), and cell stretching/extension was significantly reduced by treatment with HIF1α‐stabilizing chemical compounds (Scully et al, ). Because we observed significantly increased HIF1α expression in the rNCSCs cultured at 0.5% O 2 (Figs.…”

“…I, A,E, ). Of interest, previous studies have demonstrated that the regulatory relationship between HIF1α and SNAIL may be dependent on species and cell types (Barriga et al, ; Scully et al, ), as inhibition of HIF1α expression by morpholino injection did not affect Snail1 and Snail2 expression in neural crest cells of the Xenopus laevis embryos (Barriga et al, ), whereas HIF1α stabilization increased SNAIL2 expression in cranial neural crest cells of the chick embryos (Scully et al, ).…”

“…Previous in vivo studies have shown that hypoxia (10% O 2 ) increased proliferation and differentiation of mouse and rat NCSCs in the carotid body indirectly and non–cell‐autonomously via synaptic‐like contacts with the peripheral glomus cells (Kokovay and Temple, ; Pardal et al, ; Platero‐Luengo et al, ; Lopez‐Barneo et al, ). Furthermore, a recent in vivo study published this year demonstrated that hypoxia greatly increased the number of NCSCs in chick embryos via HIF1α‐mediated epithelial‐to‐mesenchymal transition (EMT) (Scully et al, ). In addition to in vivo studies, previous in vitro studies have also reported increased colony‐forming capacity and multilineage differentiation of NCSCs under hypoxia at 3–6% oxygen levels (Morrison et al, ).…”

Developing Cures: Targeting Ontogenesis in Cancer

“…In ontogenesis, hypoxic signaling is required for angiogenesis and development of the placenta and cardiovascular system, and deletion of HIF-1α is embryonic lethal [8, 66]. Hypoxia is also required for the production and delamination of neural crest cells, discussed earlier, and this process is normally limited by the maturation of the circulatory system [67]. In cancer, HIF signaling is involved in angiogenesis, invasion, and metastasis [9, 68] as well as in maintenance of the CSC niche [69–71].…”